ClinVar Miner

Submissions for variant NM_020822.3(KCNT1):c.2849G>A (p.Arg950Gln)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000498228 SCV000340255 uncertain significance not provided 2016-03-28 criteria provided, single submitter clinical testing
GeneDx RCV000498228 SCV000589673 pathogenic not provided 2018-06-21 criteria provided, single submitter clinical testing The R950Q variant in the KCNT1 gene has been previously reported as a de novo change in multiple individuals previously tested at GeneDx and in the published literature with epilepsy (Moller et al., 2015; Hildebrand et al., 2016). The R950Q variant is not observed in large population cohorts (Lek et al., 2016). The R950Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.
Invitae RCV000650627 SCV000772474 pathogenic Early infantile epileptic encephalopathy 14; Epilepsy, nocturnal frontal lobe, 5 2019-09-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 950 of the KCNT1 protein (p.Arg950Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in individuals affected with infantile seizures, epilepsy and developmental delay (PMID: 26122718, 27029629, 29100083). ClinVar contains an entry for this variant (Variation ID: 286710). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Arg950Leu) has been determined to be pathogenic (Invitae database). This suggests that the arginine residue is critical for KCNT1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Génétique des Maladies du Développement, Hospices Civils de Lyon RCV001004680 SCV001164136 pathogenic Early infantile epileptic encephalopathy 14 2017-02-15 criteria provided, single submitter clinical testing

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